MEKK1-Dependent Activation of the CRL4 Complex Is Important for DNA Damage-Induced Degradation of p21 and DDB2 and Cell Survival

Cullin-4 ubiquitin ligase (CRL4) complexes are differentially composed and highly dynamic protein assemblies that control many biological processes, including the global genome nucleotide excision repair (GG-NER) pathway. Here, we identified the kinase mitogen-activated protein kinase kinase kinase...

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Bibliographic Details
Published in:Molecular and cellular biology 2021-10, Vol.41 (10), p.e0008121-e0008121
Main Authors: Bacher, Susanne, Stekman, Hilda, Farah, Carla M., Karger, Annika, Kracht, Michael, Schmitz, M. Lienhard
Format: Article
Language:English
Subjects:
apoptosis
cell cycle
Cell Cycle Checkpoints
Cell Line, Tumor
Cell Survival
cullin-4
Cyclin-Dependent Kinase Inhibitor p21 - genetics
DNA - chemistry
DNA damage
DNA Damage - physiology
DNA Repair - genetics
DNA Repair - physiology
DNA-Binding Proteins - metabolism
HEK293 Cells
HeLa Cells
Humans
MAP Kinase Kinase Kinase 1 - genetics
MAP Kinase Kinase Kinase 1 - metabolism
MEKK1
mitogen-activated protein kinases
Molecular and Cellular Biology
Nuclear Proteins - metabolism
Research Article
Spotlight
Ubiquitin-Protein Ligases - metabolism
Ubiquitin-Protein Ligases - physiology
Ubiquitination
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Summary:Cullin-4 ubiquitin ligase (CRL4) complexes are differentially composed and highly dynamic protein assemblies that control many biological processes, including the global genome nucleotide excision repair (GG-NER) pathway. Here, we identified the kinase mitogen-activated protein kinase kinase kinase 1 (MEKK1) as a novel constitutive interactor of a cytosolic CRL4 complex that disassembles after DNA damage due to the caspase-mediated cleavage of MEKK1. The kinase activity of MEKK1 was important to trigger autoubiquitination of the CRL4 complex by K48- and K63-linked ubiquitin chains. MEKK1 knockdown prohibited DNA damage-induced degradation of the CRL4 component DNA-damage binding protein 2 (DDB2) and the CRL4 substrate p21 and also cell recovery and survival. A ubiquitin replacement strategy revealed a contribution of K63-branched ubiquitin chains for DNA damage-induced DDB2/p21 decay, cell cycle regulation, and cell survival. These data might also have implications for cancer, as frequently occurring mutations of MEKK1 might have an impact on genome stability and the therapeutic efficacy of CRL4-dependent immunomodulatory drugs such as thalidomide derivatives.
ISSN:0270-7306
1098-5549
1098-5549
DOI:10.1128/MCB.00081-21